Ischaemia-reperfusion injury (IRI) has been identified as a major contributor to both short and long term kidney transplant failure. Experimental evidence from the literature suggests that Erythropoietin (EPO) is tissue protective, reducing both inflammation and apoptosis following IRI. We performed a randomised, double blind, placebo controlled trial examining the tissue protective effect of high dose EPO (100,000iu over 3 days) in 39 recipients of an extended criteria donor kidney or a non-heart-beating donor kidney. The primary endpoints of the study were difference in plasma and urinary biomarker levels (NGAL, IL-18 and KIM-1) in addition to changes in gene expression. Secondary endpoints included safety, clinical data and differences in metabolomics profiles. There was no difference detected between the treatment groups in terms of biomarkers, gene expression, metabolomics profiling or clinical parameters. No adverse events related to EPO therapy were recorded. In addition, we developed a cell model of kidney transplantation using primary tubulo-epithelial cells and HMEC-1 cells, with which to confirm the protective effects of EPO. Treatment with 50U/ml one hour prior to undergoing cold hypoxia resulted in the maximum degree of tissue protection, as measured using an MTT and an LDH assay. No evidence of EPO toxicity was demonstrated. Tubulo-epithelial cells expressed EPOR mRNA and protein. No CD131 receptor could be demonstrated. In summary, EPO confers tissue protection in a cell model of kidney transplantation but this has not been shown to occur in a clinical trial using high dose EPO in recipients of marginal donor kidneys.

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A research report to the Faculty of Health Sciences, University of Witwatersrand, Johannesburg, in partial fulfillment of the requirements for the degree of Master Medicine in branch of Haematology / Donor specific crossmatching is performed prior to renal transplantation in order to determine the presence of pre-existing antibodies against donor HLA antigens which can result in hyperacute rejection. Flow cytometric crossmatching is reported in the literature to be a more sensitive and objective method of testing than the complement dependent cytotoxicity (CDC) method that is currently used in the Gauteng Province. A prospective analysis of the flow cytomeric crossmatch (FCXM) assay using the Luminex technology as the reference method was conducted. Forty-three samples were analysed. The T cell crossmatch (using a cutoff value of 2) revealed a sensitivity of 66.7%, a specificity of 83.8%, a positive predictive value (PPV) of 40% and negative predictive value (NPV) of 93.9%. The B cell crossmatch (using a cutoff value of 5) gave a sensitivity of 100%, specificity of 92.7%, and a PPV and NPV of 40 and100%, respectively. In addition, a retrospective analysis of clinical data for all patients transplanted during the period January 2008 to May 2009 was performed. Of a total of 50 patients assessed post transplant, none of the patients showed signs of hyperacute rejection, while twelve percent (12%) of patients revealed signs and symptoms suggestive of acute rejection. The validation of the flow cytometric crossmatch analysis was complex as there is no gold standard reference method. The assay was validated based on the clinical relevance of its high negative predictive value and the absence of hyperacute rejections in the clinical follow up. The rate of acute rejection found in this study is similar to that reported in literature.

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This document only includes an excerpt of the corresponding thesis or dissertation. To request a digital scan of the full text, please contact the Ruth Lilly Medical Library's Interlibrary Loan Department (rlmlill@iu.edu).

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Background Organ donation may occur after death determination by neurological criteria or by circulatory criteria (DCC). This thesis evaluates two controversial practices specific to DCC: (1) antemortem heparin administration to DCC donors with the aim of improving organ function, and (2) cardiac donation after DCC, which has not yet been adopted in Canada. Objectives (1) Describe antemortem heparin practices in DCC and explore its effects on transplant outcomes. (2) Describe the opinions, concerns, and insights of Canadian healthcare providers and the public regarding cardiac DCC. Methods Project 1: Systematic review and meta-regression analysis of published studies examining antemortem heparin in DCC donation. Projects 2 and 3: A qualitative interview study to evaluate the perspectives of healthcare providers and a mixed methods study involving focus groups with members of the Canadian public. Results Project 1: We found broad variability in the dosing and timing of heparin administration in DCC. While there were no clinical trials, meta-regression analysis detected no benefit to antemortem heparin in liver transplantation. Projects 2 and 3: Among healthcare providers, we found broad support for cardiac DCC but concerns about potential lack of support by the public. Among members of the public, we found majority support for cardiac DCC with priorities including respect for the wishes of dying individuals and ensuring that they are treated with dignity. Conclusions While preliminary results failed to demonstrate the benefit of antemortem heparin administration to DCC donors, high-quality clinical trials are needed to better evaluate the risks and benefits. Regarding cardiac DCC, despite healthcare providers’ concerns about lack of public support, most public stakeholders engaged in our study were supportive. The multi-modal approach of this thesis may serve as a model for evaluating other controversial practices in deceased organ donation. / Thesis / Candidate in Philosophy / Organs that are donated and transplanted from deceased individuals save thousands of lives every year. Some organs are donated after death by circulatory criteria (i.e., after the heart has stopped beating). We evaluated two controversial practices in organ donation after death is determined by circulatory criteria: (1) giving heparin, a blood thinner, just before death, and (2) heart donation after death is determined by circulatory criteria. In Project 1, our review of existing literature showed broad differences in heparin use around the time of death and heparin had no benefits on liver transplant outcomes. In Project 2, we found that healthcare providers and members of the public supported heart donation after death is determined by circulatory criteria but expressed concerns that are important to consider when establishing heart donation programs. Our approach of using multiple methods to evaluate practices in organ donation can serve as one model for evaluating other controversial practices in organ donation.

Thesis (DScMedSc (Medical Sciences)--University of Stellenbosch, 2010. / Bibliography / ENGLISH ABSTRACT: See full text for abstract / AFRIKAANSE OPSOMMING: Geen opsomming was ingehandig met tesis

published_or_final_version / Surgery / Doctoral / Doctor of Philosophy